Affinage

TOP1

DNA topoisomerase 1 · UniProt P11387

Length
765 aa
Mass
90.7 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOP1 is a type IB DNA topoisomerase that relieves torsional stress during DNA replication and transcription by transiently nicking one DNA strand through a covalent 3'-phosphotyrosyl cleavage intermediate (TOP1 cleavage complex, TOP1cc) (PMID:27257064, PMID:35013228). Structural and mutagenic analysis of an archaeal ortholog defines an open-to-closed conformational transition gated by a conserved hinge tyrosine that permits DNA entry and underlies camptothecin sensitivity (PMID:35013228). TOP1 acts coordinately with TOP2 at replication forks: loss of either alone is tolerated, but combined inactivation blocks fork progression and replication initiation and triggers checkpoint activation, establishing complementary topoisomerase roles in DNA replication from yeast to vertebrates (PMID:2997777, PMID:17671091, PMID:41791707). Beyond replication, TOP1 catalytic activity promotes a repressed chromatin state at rDNA and telomeres, where its loss elevates histone H4 acetylation and derepresses proximal genes (PMID:18272174, PMID:12215413), and it cooperates with R-loops at highly expressed genes to generate transcription-associated double-strand breaks (PMID:38375218). TOP1ccs are normally transient but become genotoxic when trapped — by camptothecin or by TOP1 action at genome-embedded ribonucleotides — generating recombination, chromosomal instability, and a characteristic short-deletion mutational signature (ID4/ID-TOP1) produced through a sequential double-cleavage mechanism within tandem repeats (PMID:24574527, PMID:25830313, PMID:27257064, PMID:35140396). Trapped TOP1ccs are removed by redundant pathways: TDP1-mediated hydrolysis of the phosphotyrosyl bond, the ERCC1-XPF/RPA nucleolytic (NER) branch, MUS81 cleavage of proteolytically processed TOP1cc, and NHEJ, with TDP1 activity regulated by CDK1 phosphorylation at Ser61 during mitosis (PMID:26025908, PMID:30778235, PMID:37194054, PMID:39014228). PARP1 is activated by trapped TOP1ccs and PARylates TOP1, controlling its nucleolar-to-nucleoplasmic dynamics and counteracting camptothecin-induced TOP1cc stabilization (PMID:27466387). A recurrent NUP98-TOP1 fusion from the t(11;20) translocation is associated with therapy-related myelodysplastic syndrome/AML (PMID:10556215), and clinically acquired TOP1 point mutations confer resistance to TOP1-inhibitor antibody-drug-conjugate payloads (PMID:39745368).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1985 High

    Established that TOP1 encodes DNA topoisomerase I and serves an auxiliary, partially redundant role to TOP2 in genome metabolism, resolving whether either enzyme is individually essential.

    Evidence Gene disruption and synthetic-lethality genetics in S. cerevisiae with temperature-sensitive top2 alleles

    PMID:2997777

    Open questions at the time
    • Did not define the molecular reactions TOP1 and TOP2 share
    • Mechanism of synthetic lethality not resolved at this stage
  2. 2002 High

    Showed that covalent TOP1-DNA adducts are removed by two redundant pathways feeding recombinational restart, defining the core logic of TOP1cc repair.

    Evidence Genetic epistasis of tdp1 and rad1-rad10 mutants with camptothecin sensitivity in S. cerevisiae

    PMID:12368472

    Open questions at the time
    • Biochemical step performed by each pathway not reconstituted here
    • Relative pathway contribution in mammals not addressed
  3. 2002 Medium

    Linked TOP1 catalytic activity to chromatin repression at rDNA, extending its role beyond torsional relief.

    Evidence Histone acetylation and chromatin accessibility assays in top1 vs sir2 deletion strains of S. cerevisiae

    PMID:12215413

    Open questions at the time
    • Mechanism connecting catalytic activity to histone acetylation unclear
    • Single lab, yeast only
  4. 2007 High

    Demonstrated that TOP1 and TOP2 act coordinately within a narrow region around moving replication forks to prevent fork block and sister entanglement, defining where the auxiliary relationship operates.

    Evidence ChIP of replicating chromosomes plus checkpoint and γH2AX assays in top1/top2 mutants of S. cerevisiae

    PMID:17671091

    Open questions at the time
    • Did not distinguish supercoil relief from decatenation contributions precisely
    • Vertebrate generality untested at this point
  5. 2008 Medium

    Extended TOP1's chromatin-repressive role to telomeres, showing catalytic activity is required to maintain repressed subtelomeric chromatin.

    Evidence ChIP for TOP1 binding and histone marks plus expression profiling with a Y727F catalytic-dead mutant in S. cerevisiae

    PMID:18272174

    Open questions at the time
    • Direct causal link between strand cleavage and acetylation state not established
    • Single lab
  6. 2011 High

    Identified SUMO/STUbL signaling (Rad60, Nse2) as suppressors of spontaneous TOP1ccs that channel lesions into the NER-endonuclease repair branch, adding a regulatory layer to TOP1cc tolerance.

    Evidence Genetic epistasis and ChIP-qPCR detection of Top1ccs in S. pombe

    PMID:21408210

    Open questions at the time
    • Direct SUMO/ubiquitin modification of TOP1 not demonstrated here
    • Mammalian counterpart not tested
  7. 2014 High

    Showed that TOP1ccs are physiologically stabilized and reversible at the rDNA replication fork barrier in a Fob1/Tof2-dependent manner, linking site-specific TOP1cc to rDNA stability.

    Evidence ChIP detection of Top1ccs at the rRFB, ectopic constructs, and fob1/tof2 epistasis in S. cerevisiae

    PMID:24574527

    Open questions at the time
    • Function of these reversible Top1ccs in rDNA maintenance not fully defined
    • Relevance to mammalian rDNA unknown
  8. 2015 Medium

    Established that trapped TOP1ccs are recombinogenic, driving crossovers and tandem-array instability, connecting TOP1cc trapping to genome instability.

    Evidence Sectoring/LOH assays, chromosome microarrays, and long-term subculturing in S. cerevisiae

    PMID:25830313

    Open questions at the time
    • Exact lesion converting Top1cc to a recombination substrate not defined
    • Single organism
  9. 2015 High

    Reconstituted an ERCC1-XPF/RPA nucleolytic pathway for repairing the TOP1 3'-phosphotyrosyl lesion, establishing a TDP1-independent NER-based repair route in mammals.

    Evidence In vitro nuclease and repair-synthesis reconstitution on Tyr-nick substrates plus co-localization in CPT-treated cells

    PMID:26025908

    Open questions at the time
    • In vivo relative contribution vs TDP1 not quantified here
    • Substrate used intact rather than full protein-DNA crosslink
  10. 2016 High

    Defined the sequential double-cleavage mechanism by which TOP1 activity at ribonucleotides generates short tandem-repeat deletions, explaining a mutagenic consequence of TOP1 catalysis.

    Evidence Parallel in vitro cleavage/ligation assays and in vivo yeast mutagenesis with systematic substrate variation

    PMID:27257064

    Open questions at the time
    • Did not establish frequency of this process in mammalian genomes
    • Determinants of intermediate realignment beyond complementarity not exhausted
  11. 2016 High

    Showed that PARP1 PARylates trapped TOP1 to control its subnuclear dynamics and counteract TOP1cc stabilization, defining a post-translational regulatory mechanism for TOP1cc resolution.

    Evidence Live-cell FRAP of GFP-TOP1 with PARP inhibitors and W205/N722S mutagenesis in human cells

    PMID:27466387

    Open questions at the time
    • Identity of PARylated residues on TOP1 not mapped
    • Downstream repair enzymes coupled to PARylation not defined
  12. 2019 High

    Identified Apn2 as an additional 3'-end processing enzyme acting on TOP1cc and ribonucleotide-derived termini, broadening the repertoire of TOP1cc-resolving activities.

    Evidence Genetic epistasis plus biochemical assays with purified Apn2 on defined substrates in S. cerevisiae

    PMID:30778235

    Open questions at the time
    • Mammalian ortholog contribution not addressed
    • Hierarchy relative to TDP1 in vivo unclear
  13. 2019 Medium

    Demonstrated that NHEJ produces large TOP1cc-dependent deletions outside replication, including in quiescent cells, showing TOP1 lesions cause DSBs independent of fork passage.

    Evidence Genetic analysis of NHEJ mutants and deletion-junction characterization in quiescent S. cerevisiae

    PMID:31636207

    Open questions at the time
    • Origin of the underlying DSBs not directly visualized
    • Single organism
  14. 2022 High

    Established that in mammals TOP1 action at unrepaired embedded ribonucleotides generates the ID4/ID-TOP1 indel signature contributing to cancer and germline de novo mutations, linking the yeast mechanism to human disease.

    Evidence Genome sequencing of ribonucleotide-excision-repair-deficient mammals, signature analysis, and TOP1 inhibition

    PMID:35140396

    Open questions at the time
    • Tissue-specific drivers of the signature not fully mapped
    • Therapeutic exploitation untested
  15. 2022 High

    Resolved the conformational mechanism of catalysis, showing a hinge tyrosine gates an open-to-closed transition required for activity and camptothecin sensitivity.

    Evidence Crystal structure of apo archaeal CsTOP1 with directed hinge mutagenesis and CPT sensitivity assays

    PMID:35013228

    Open questions at the time
    • Structure is of an archaeal ortholog, not human TOP1
    • Dynamics during strand cleavage not captured
  16. 2022 Medium

    Dissected the human TOP1cc DSB-conversion pathway, showing MUS81 (not APEX) generates excess DSBs in TDP1-deficient cells, clarifying parallel repair routing.

    Evidence Genome-wide CRISPR screens and isogenic TDP1/MUS81 and TDP1/APEX KO cell lines with DNA damage assays

    PMID:35869071

    Open questions at the time
    • Did not define how TOP1cc is dislodged before MUS81 cleavage
    • Single lab
  17. 2023 High

    Showed MUS81 requires proteolytic processing of TOP1 before cleaving TOP1cc and acts non-redundantly with TDP1, defining substrate requirements for the nucleolytic branch.

    Evidence In vitro MUS81 cleavage assays with intact vs processed TOP1-DNA substrates plus double-KO cell assays

    PMID:37194054

    Open questions at the time
    • Protease responsible for TOP1 processing not identified here
    • In vivo ordering of processing and cleavage not resolved
  18. 2023 Medium

    Established that TDP1 suppresses chromosomal translocations from transcription-associated TOP1 DSBs repaired error-prone by MRN/NHEJ, connecting TOP1cc repair to genome rearrangement.

    Evidence Loss-of-function genetics with cytogenetic translocation analysis and MRN/NHEJ epistasis in human cells

    PMID:37945566

    Open questions at the time
    • Genomic loci of recurrent translocations not mapped
    • Single lab
  19. 2024 High

    Identified CDK1 phosphorylation of TDP1 at Ser61 as the switch enabling MUS81-dependent mitotic TOP1cc repair, defining cell-cycle regulation of the repair choice.

    Evidence CDK1 kinase assay, TDP1-S61A mutant cells, live imaging, and MUS81 epistasis in human cells

    PMID:39014228

    Open questions at the time
    • Other mitotic substrates and regulators not excluded
    • Mechanism of S61A chromatin trapping incompletely defined
  20. 2024 Medium

    Showed TOP1 and R-loops cooperate at highly expressed genes to generate transcriptional DSBs implicated in early cancer changes, linking TOP1 catalysis to transcription-associated genome instability.

    Evidence Genome-wide DSB, R-loop, and TOP1cc mapping with TOP1 and R-loop depletion in human cells

    PMID:38375218

    Open questions at the time
    • Causal step from R-loop/TOP1 to DSB not biochemically reconstituted
    • Single lab
  21. 2025 Medium

    Functionally characterized clinically acquired TOP1 mutations that reduce activity and covalent DNA binding to confer resistance to TOP1-inhibitor ADC payloads, providing a mechanism of acquired therapy resistance.

    Evidence Enzymatic, covalent-binding, and in vitro drug-resistance assays on recombinant mutant TOP1 with plasma genotyping

    PMID:39745368

    Open questions at the time
    • In vivo tumor resistance not directly demonstrated
    • Structural basis of each mutation not resolved
  22. 2026 Medium

    Confirmed in vertebrate cells that TOP1 and TOP2 act complementarily in both replication initiation and progression, generalizing the yeast auxiliary relationship to higher eukaryotes.

    Evidence Conditional TOP1 depletion plus TOP2 inhibition with DNA fiber assays and cell cycle analysis in DT40 cells

    PMID:41791707

    Open questions at the time
    • Did not distinguish supercoiling vs decatenation contributions at initiation
    • Single cell-line model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TOP1 PARylation, proteolytic processing, and cell-cycle signaling are integrated to select among the multiple competing TOP1cc repair pathways in human cells remains unresolved.
  • No unified model coordinating TDP1, ERCC1-XPF, MUS81, Apn2, and NHEJ choice
  • PARylation target residues on human TOP1 unmapped
  • Structural model of human TOP1cc engagement by each repair enzyme lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140097 catalytic activity, acting on DNA 3 GO:0016853 isomerase activity 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2 R-HSA-69306 DNA Replication 2
Partners
BTBD1BTBD2ERCC1MUS81PARP1RPATDP1XPF

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 Yeast TOP1 encodes DNA topoisomerase I; deletion mutants (delta top1) are viable, but delta top1 top2-ts double mutants are inviable even when mitotic progression is blocked, demonstrating that Top1 serves an auxiliary role to Top2 in yeast DNA metabolism. Gene disruption/deletion in S. cerevisiae, complementation, temperature-shift experiments with synchronous cultures Proceedings of the National Academy of Sciences of the United States of America High 2997777
2002 In S. cerevisiae, Tdp1 (tyrosyl-DNA phosphodiesterase) and the Rad1-Rad10 structure-specific endonuclease act as two primary, redundant pathways to remove covalent Top1-DNA adducts (Top1 cleavage complexes) at replication forks; tdp1 rad1 double mutants are highly sensitive to camptothecin and show a TOP1-dependent growth delay. Both pathways funnel into RAD52/RAD51/RAD50-dependent recombination for replication restart. Genetic epistasis analysis (double/triple mutants), camptothecin sensitivity assays in S. cerevisiae Proceedings of the National Academy of Sciences of the United States of America High 12368472
2007 Top1 and Top2 act within a ~600-bp region spanning moving replication forks in S. cerevisiae. TOP1 ablation alone does not block fork progression or activate the Rad53 checkpoint, but top1 top2 double mutants exhibit replication fork block, fork processing, and Rad53/γH2AX activation in S phase, demonstrating that Top1 and Top2 act coordinately to relieve torsional stress and prevent sister chromatid entanglement at forks. Chromatin immunoprecipitation (ChIP) of replicating chromosomes, genetic analysis of top1, top2, and top1 top2 mutants, checkpoint kinase (Rad53) phosphorylation assays, γH2AX detection Genes & development High 17671091
2008 Top1 binds to and is catalytically active at telomeric DNA repeats in S. cerevisiae; deletion of TOP1 or expression of catalytically inactive Top1-Y727F increases H4 histone acetylation at subtelomeric regions and activates transcription of telomere-proximal genes, indicating that Top1 catalytic activity promotes a repressed chromatin state at telomeres. Chromatin immunoprecipitation (ChIP) for Top1 binding and histone modifications, expression profiling (microarray), TOP1 deletion and Y727F catalytic-dead mutant Journal of molecular biology Medium 18272174
2011 In fission yeast, STUbL (SUMO-targeted ubiquitin ligase), Rad60, and the Nse2 SUMO E3 ligase suppress spontaneous Top1-mediated DNA damage (Top1 cleavage complexes). Cells lacking STUbL activity become dependent on Tdp1, and Top1ccs detected by ChIP-qPCR are elevated when STUbL, Rad60, or Nse2 activity is absent. Tdp1 and Rad16-Swi10 (NER endonuclease) constitute the two major Top1cc repair pathways, with STUbL/Rad60/Nse2 facilitating the Rad16-Swi10 branch. Genetic epistasis, chromatin immunoprecipitation (ChIP)-qPCR to detect Top1ccs, camptothecin sensitivity assays in S. pombe PLoS genetics High 21408210
2014 Top1 cleavage complexes (Top1ccs) are specifically stabilized at the ribosomal replication fork barrier (rRFB) in S. cerevisiae in a strand-specific, replication-independent manner requiring Fob1 and Tof2; these Top1ccs are reversible (not subject to Tdp1 or Mus81 repair) and their presence correlates with Top1-dependent rDNA stability. ChIP detection of Top1ccs at rRFB, ectopic rRFB constructs, genetic analysis with fob1 and tof2 mutants, Tdp1/Mus81 epistasis in S. cerevisiae Nucleic acids research High 24574527
2015 Trapping of the Top1 cleavage complex (Top1cc) in S. cerevisiae (via camptothecin or top1-T722A allele) causes a 5–10-fold increase in reciprocal crossover events and greatly elevated instability within rDNA and CUP1 tandem arrays, with evidence that recombinogenic lesions arise during or after DNA synthesis. Sectoring assay for loss of heterozygosity, chromosome microarrays, sub-culturing for 250 generations, genetic analysis in S. cerevisiae PLoS genetics Medium 25830313
2015 ERCC1-XPF endonuclease and RPA participate in NER-mediated repair of Top1-attached nick DNA lesions (3'-phosphotyrosyl bond). ERCC1-XPF cleaves a Tyr-nick DNA substrate in vitro in the presence of RPA, and repair DNA synthesis of these lesions occurs with NER factors (ERCC1-XPF, RPA, DNA pol δ, FEN1, DNA ligase 1). In vitro nuclease assay on Tyr-nick DNA substrate, co-localization of ERCC1-XPF and RPA in CPT-treated cells, in vitro repair synthesis reconstitution Carcinogenesis High 26025908
2016 PARP1 is activated by trapped Top1 cleavage complexes (Top1cc) and PARylates Top1. Using live-cell FRAP of GFP-tagged human Top1 and PARP inhibitors (ABT-888/Veliparib), PARP inhibition was shown to delocalize Top1 from nucleolus to nucleoplasm and to markedly increase the CPT-induced immobile/bound fraction of Top1 (Top1cc) genome-wide, indicating that PAR-modification of Top1 counteracts CPT-induced stabilization of Top1cc. Top1 residues Trp205 and Asn722 are critical for subnuclear dynamics; Top1-N722S is restricted to the nucleolus under CPT due to deficient PARylation. Live-cell imaging of GFP-tagged Top1, FRAP with kinetic modelling, PARP inhibitor treatment, site-directed mutagenesis (W205, N722S) Nucleic acids research High 27466387
2016 Top1-dependent ribonucleotide-associated deletions in yeast arise through a sequential double-cleavage mechanism: Top1 cleaves at a ribonucleotide, the resulting intermediate realigns within a tandem repeat, and Top1 ligates the realigned nick, generating a single-repeat deletion. Deletion frequency is inversely related to the distance between two Top1 cleavage sites, and complementarity downstream of the gap promotes deletions more effectively than upstream complementarity. Parallel in vitro Top1 cleavage/ligation assays and in vivo yeast mutagenesis assays, systematic variation of substrate distances and complementarity Nucleic acids research High 27257064
2019 Top1cc-dependent large deletions (~100 bp) in yeast are produced by the NHEJ pathway and require Top1cc removal from DNA ends; these events accumulate in quiescent cells, suggesting that causative DSBs arise outside replication context. Joining of ends from distinct Top1-associated DSBs via NHEJ deletes the intervening sequence. Genetic analysis of NHEJ mutants in S. cerevisiae, characterization of deletion junctions, quiescence experiments Proceedings of the National Academy of Sciences of the United States of America Medium 31636207
2019 Yeast Apn2 (AP endonuclease 2) resolves Top1-mediated phosphotyrosine-DNA conjugates (Top1cc), terminal 2',3'-cyclic phosphates, and their hydrolyzed products at 3' DNA ends, and suppresses 2-bp slippage mutagenesis in RNH201-deficient cells, defining Apn2 as an alternative Top1cc repair enzyme. Genetic epistasis, biochemical assays with purified Apn2 on Top1cc and cyclic-phosphate substrates in S. cerevisiae Nature structural & molecular biology High 30778235
2022 Defective ribonucleotide excision repair in mammals leads to accumulation of genome-embedded ribonucleotides, at which TOP1 activity generates short (2–5 bp) deletions (ID4/ID-TOP1 mutation signature) at TNT motifs; this transcription-associated mutagenesis process contributes to cancer somatic mutations and germline de novo indels. Genome sequencing of cancer and germline samples from ribonucleotide excision repair-deficient mammals, mutational signature analysis, functional TOP1 inhibition experiments Nature High 35140396
2022 Archaeal CsTOP1 (a structural ortholog of eukaryotic TOP1) adopts an open conformation in apo form, with the hinge loop (5-residue junction between CAP and CAT modules) permitting rotation that allows DNA entry. A conserved tyrosine near the hinge mediates transition to the closed conformation upon DNA binding; directed mutagenesis of hinge residues confirmed this flexibility is required for activity and linked to camptothecin sensitivity. Crystal structure of apo CsTOP1, directed mutagenesis of hinge residues, camptothecin sensitivity assays Nature communications High 35013228
2022 Whole-genome CRISPR screens and co-deficient cell lines demonstrated that MUS81 mediates the generation of excess double-strand breaks (DSBs) in TDP1-KO cells exposed to Top1 poisons; APEX1/2 are synthetically lethal with TDP1 but do not reduce DSB formation in TDP1-KO cells. Top1cc can be resolved directly by TDP1 or converted to DSBs and repaired by homologous recombination. Genome-wide CRISPR screens, generation of co-deficient cell lines (TDP1/MUS81 and TDP1/APEX KO), DNA damage assays Nature communications Medium 35869071
2023 TDP1 suppresses chromosomal translocations arising from transcription-associated TOP1-induced DSBs; error-prone repair of these breaks relies on the MRN complex and canonical NHEJ. TDP1 loss leads to increased chromosome rearrangements specifically linked to transcription-coupled TOP1 activity. Loss-of-function genetics in human cells, cytogenetic analysis of translocations, epistasis with MRN and NHEJ factors Nature communications Medium 37945566
2023 MUS81 endonuclease can efficiently cleave DNA substrates bearing proteolytically processed (but not intact) TOP1, indicating TOP1 must be dislodged or partially degraded before MUS81 cleavage. MUS81 and TDP1 play independent, non-redundant roles in repair of CPT-induced TOP1-DPC lesions. In vitro MUS81 cleavage assays with fluorescein-, streptavidin-, and proteolytically processed TOP1-modified DNA substrates; nuclear extract assays; TDP1/MUS81 double-KO cell sensitivity assays BMC biology High 37194054
2024 CDK1 phosphorylates TDP1 at Ser61 during mitosis; TDP1-S61A (non-phosphorylatable) is trapped on mitotic chromosomes and causes DNA damage and mitotic defects. Top1cc repair in mitosis occurs via a MUS81-dependent mechanism, and TDP1-S61A enrichment at common fragile sites over-stimulates MUS81-dependent chromatid breaks, leading to anaphase bridges, micronuclei, and 53BP1 nuclear bodies in G1. CDK1 kinase assay identifying TDP1 S61 phosphorylation, TDP1-S61A mutant cell lines, live imaging, γH2AX/53BP1 focus analysis, MUS81 epistasis The EMBO journal High 39014228
2024 TOP1 and R-loops are enriched at highly expressed genes where transcriptional DSBs occur; depletion of R-loops or TOP1 significantly reduces transcription-associated DSBs at these loci, establishing that TOP1 and R-loops cooperate in transcriptional DSB formation and contribute to early molecular changes driving cancer development. Genome-wide DSB mapping, R-loop mapping, TOP1cc mapping, TOP1 depletion and R-loop depletion in human cells iScience Medium 38375218
2025 TOP1 mutations (S57C, R364H, W401C, G359E) arising under selective pressure from ADC therapy in metastatic breast cancer patients exhibit reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1-inhibitor payloads SN38 and deruxtecan, functionally characterizing resistance-associated TOP1 mutations. Functional characterization of recombinant mutant TOP1 proteins (enzymatic activity assays, covalent DNA binding assays, in vitro drug resistance assays), plasma-based genotyping Clinical cancer research Medium 39745368
2010 TOP1 interacts with BTBD1 and BTBD2; this interaction requires human TOP1 residues 236 and 237. The same residues are required for TOP1 to enhance infectivity of HIV-1 virions when expressed in African Green Monkey producer cells. RNAi knockdown of BTBD2 in AGM and human cells increased HIV-1 permissiveness 2–3-fold. Co-IP/interaction assays with TOP1 point mutants (residues 236/237), RNAi knockdown of BTBD2, HIV-1 infectivity assays Virology journal Low 21092135
2026 In vertebrate (chicken DT40) cells, TOP1 depletion alone does not affect replication fork progression, and TOP2 inhibition (ICRF193) alone also has no effect; however, combined TOP1 depletion plus TOP2 inhibition nearly abolishes DNA replication, causing S-phase arrest and apoptosis. TOP1 depletion combined with TOP2 poison (etoposide) impairs replication initiation rather than elongation. This demonstrates complementary roles of TOP1 and TOP2 in both initiation and progression of DNA replication in vertebrates. Conditional TOP1 depletion in DT40 cells, ICRF193 and etoposide pharmacological inhibition, DNA fiber assays for fork progression, cell cycle analysis The Journal of biological chemistry Medium 41791707
2002 Deletion of TOP1 in S. cerevisiae increases histone H4 acetylation at the rDNA locus and renders rDNA chromatin more accessible, similar to sir2 mutants, indicating that Top1 activity promotes a repressed chromatin state at rDNA. Chromatin accessibility assays, histone acetylation analysis at rDNA in top1 and sir2 deletion strains of S. cerevisiae Journal of molecular biology Medium 12215413
1999 The t(11;20)(p15;q11) chromosomal translocation produces an NUP98-TOP1 chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I (TOP1), with the breakpoint in TOP1 occurring within the gene; this fusion is associated with therapy-related myelodysplastic syndrome/acute myeloid leukemia. Cloning and sequencing of t(11;20) translocation breakpoints, RT-PCR characterization of fusion transcript in patient samples Blood Medium 10556215

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage. Proceedings of the National Academy of Sciences of the United States of America 183 12368472
1985 Cloning of yeast TOP1, the gene encoding DNA topoisomerase I, and construction of mutants defective in both DNA topoisomerase I and DNA topoisomerase II. Proceedings of the National Academy of Sciences of the United States of America 163 2997777
2007 Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation. Genes & development 136 17671091
2015 Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy. Biomolecules 116 26287259
1990 HPR1, a novel yeast gene that prevents intrachromosomal excision recombination, shows carboxy-terminal homology to the Saccharomyces cerevisiae TOP1 gene. Molecular and cellular biology 116 2181275
1999 The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 86 10556215
2022 Signatures of TOP1 transcription-associated mutagenesis in cancer and germline. Nature 76 35140396
2002 The origin recognition complex marks a replication origin in the human TOP1 gene promoter. The Journal of biological chemistry 76 12004060
2012 Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (Tdp1)-topoisomerase I (Top1) inhibitors. Journal of medicinal chemistry 63 22536944
2014 Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. Molecular cancer therapeutics 61 25522766
2004 Analgesia: morphine-pathway block in top1 poppies. Nature 61 15386001
2016 Poly(ADP-ribose) polymers regulate DNA topoisomerase I (Top1) nuclear dynamics and camptothecin sensitivity in living cells. Nucleic acids research 59 27466387
2015 Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity. European journal of medicinal chemistry 57 26312433
2010 Exon array analyses across the NCI-60 reveal potential regulation of TOP1 by transcription pausing at guanosine quartets in the first intron. Cancer research 56 20215517
2012 Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1). Journal of medicinal chemistry 55 23259865
2010 TOP1 and 2, polysaccharides from Taraxacum officinale, attenuate CCl(4)-induced hepatic damage through the modulation of NF-kappaB and its regulatory mediators. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 51 20170702
2019 The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib. Clinical cancer research : an official journal of the American Association for Cancer Research 49 31409613
2022 TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor. Molecular cancer therapeutics 45 35439320
2018 Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents. Journal of medicinal chemistry 45 30336023
2015 Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)-tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors. Journal of medicinal chemistry 45 25811317
2011 SUMO-targeted ubiquitin ligase, Rad60, and Nse2 SUMO ligase suppress spontaneous Top1-mediated DNA damage and genome instability. PLoS genetics 44 21408210
2022 TDP1-independent pathways in the process and repair of TOP1-induced DNA damage. Nature communications 41 35869071
2021 Top1-PARP1 association and beyond: from DNA topology to break repair. NAR cancer 39 33981998
2024 Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients with Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 38 38709212
2000 Genetic analysis of the Saccharomyces cerevisiae Sgs1 helicase defines an essential function for the Sgs1-Top3 complex in the absence of SRS2 or TOP1. Molecular & general genetics : MGG 37 11016837
2017 The Top1 paradox: Friend and foe of the eukaryotic genome. DNA repair 33 28641942
2008 Global transcription regulation by DNA topoisomerase I in exponentially growing Saccharomyces cerevisiae cells: activation of telomere-proximal genes by TOP1 deletion. Journal of molecular biology 33 18272174
2025 TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients with Metastatic Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 32 39745368
2023 Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us. International journal of molecular sciences 32 37108395
2019 Apn2 resolves blocked 3' ends and suppresses Top1-induced mutagenesis at genomic rNMP sites. Nature structural & molecular biology 31 30778235
2017 Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? American journal of cancer research 30 28337384
2021 Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway. Cancers 29 34439157
2014 TDP1/TOP1 Ratio as a Promising Indicator for the Response of Small Cell Lung Cancer to Topotecan. Journal of cancer science & therapy 29 25232464
2018 Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes. Journal of medicinal chemistry 27 29290109
2015 Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast. PLoS genetics 26 25830313
2012 TOP1 gene copy numbers in colorectal cancer samples and cell lines and their association to in vitro drug sensitivity. Scandinavian journal of gastroenterology 26 22171973
2007 Seizure suppression by top1 mutations in Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 17360915
2015 Repair synthesis step involving ERCC1-XPF participates in DNA repair of the Top1-DNA damage complex. Carcinogenesis 25 26025908
2021 Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer. Journal of medicinal chemistry 24 34008967
2022 Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states. Nature communications 23 35013228
2013 Mechanisms of topoisomerase I (TOP1) gene copy number increase in a stage III colorectal cancer patient cohort. PloS one 23 23577133
2018 A polysaccharide from Antrodia cinnamomea mycelia exerts antitumor activity through blocking of TOP1/TDP1-mediated DNA repair pathway. International journal of biological macromolecules 22 30267816
2014 Reversible Top1 cleavage complexes are stabilized strand-specifically at the ribosomal replication fork barrier and contribute to ribosomal DNA stability. Nucleic acids research 22 24574527
2022 Immunogenicity of small-cell lung cancer associates with STING pathway activation and is enhanced by ATR and TOP1 inhibition. Cancer medicine 21 35957613
2009 Relations between strain and gender dependencies of irinotecan toxicity and UGT1A1, CES2 and TOP1 expressions in mice. Toxicology letters 19 19931604
2002 Acetylation and accessibility of rDNA chromatin in Saccharomyces cerevisiae in (Delta)top1 and (Delta)sir2 mutants. Journal of molecular biology 17 12215413
2021 Abraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage. Nature communications 16 34272385
2020 Synthetic lethal targeting of TET2-mutant hematopoietic stem and progenitor cells (HSPCs) with TOP1-targeted drugs and PARP1 inhibitors. Leukemia 16 32572188
2020 Implications of Topoisomerase (TOP1 and TOP2α) Expression in Patients With Breast Cancer. In vivo (Athens, Greece) 16 33144457
2019 Deletions associated with stabilization of the Top1 cleavage complex in yeast are products of the nonhomologous end-joining pathway. Proceedings of the National Academy of Sciences of the United States of America 16 31636207
2018 Camptothecin Efficacy to Poison Top1 Is Altered by Bisphenol A in Mouse Embryonic Fibroblasts. Chemical research in toxicology 15 29799191
2006 Retroviral integration site analysis identifies ICSBP as a collaborating tumor suppressor gene in NUP98-TOP1-induced leukemia. Experimental hematology 15 16939812
2024 TOP1 and R-loops facilitate transcriptional DSBs at hypertranscribed cancer driver genes. iScience 14 38375218
2020 The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2. Molecular cancer therapeutics 14 32430490
2023 TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription. Nature communications 12 37945566
2017 Effects of camptothecin or TOP1 overexpression on genetic stability in Saccharomyces cerevisiae. DNA repair 12 28961461
2016 Parallel analysis of ribonucleotide-dependent deletions produced by yeast Top1 in vitro and in vivo. Nucleic acids research 12 27257064
2003 Both NUP98/TOP1 and TOP1/NUP98 transcripts are detected in a de novo AML with t(11;20)(p15;q11). Genes, chromosomes & cancer 12 12874791
2023 MUS81 cleaves TOP1-derived lesions and other DNA-protein cross-links. BMC biology 11 37194054
2003 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones and related compounds as TOP1-targeting agents: influence of structure on the ternary cleavable complex formation. Bioorganic & medicinal chemistry letters 11 14505635
2000 Carrot cells contain two top1 genes having the coding capacity for two distinct DNA topoisomerases I. Journal of experimental botany 11 11141172
2024 Neopterin mediates sleep deprivation-induced microglial activation resulting in neuronal damage by affecting YY1/HDAC1/TOP1/IL-6 signaling. Journal of advanced research 10 39029901
2016 Interplay between Top1 and Mms21/Nse2 mediated sumoylation in stable maintenance of long chromosomes. Current genetics 10 27872982
2015 TOP1 gene copy numbers are increased in cancers of the bile duct and pancreas. Scandinavian journal of gastroenterology 10 25615400
2020 TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy. Cancers 9 32028591
2015 A phase II study of weekly irinotecan in patients with locally advanced or metastatic HER2- negative breast cancer and increased copy numbers of the topoisomerase 1 (TOP1) gene: a study protocol. BMC cancer 9 25885574
2015 Dimerization and thiol sensitivity of the salicylic acid binding thimet oligopeptidases TOP1 and TOP2 define their functions in redox-sensitive cellular pathways. Frontiers in plant science 9 26042129
2003 Generation of the NUP98-TOP1 fusion transcript by the t(11;20) (p15;q11) in a case of acute monocytic leukemia. Cancer genetics and cytogenetics 9 12645654
2002 Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15). Genes, chromosomes & cancer 9 11979559
2024 TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes. The EMBO journal 8 39014228
2022 TOP1 CAD-seq: A protocol to map catalytically engaged topoisomerase 1 in human cells. STAR protocols 8 35942340
2015 Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA. Cell cycle (Georgetown, Tex.) 8 26716562
2023 Atypical genotoxicity of carcinogenic nickel(II): Linkage to dNTP biosynthesis, DNA-incorporated rNMPs, and impaired repair of TOP1-DNA crosslinks. The Journal of biological chemistry 7 37890780
2021 TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors. Pharmacological research 7 34560251
2024 Discovery of Indolo[3,2-c]isoquinoline Derivatives as Novel Top1/2 Dual Inhibitors with Orally Efficacious Antitumor Activity and Low Toxicity. Journal of medicinal chemistry 6 39106476
2017 Genetic evidence for functional interaction of Smc5/6 complex and Top1 with spatial frequency of replication origins required for maintenance of chromosome stability. Current genetics 6 28204881
2025 MicroRNA-24-3p targeting Top1 in perirenal fat is involved in circulating inflammation and high cardiovascular disease risk in patients with primary aldosteronism. Journal of translational medicine 5 40102901
2023 Evolution of TOP1 and TOP1MT Topoisomerases in Chordata. Journal of molecular evolution 5 36651963
2022 Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBβ3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer. Journal of personalized medicine 5 36294786
2021 TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data. Lung cancer (Amsterdam, Netherlands) 5 34974222
2020 Top1 and Top2 promote replication fork arrest at a programmed pause site. Genes & development 5 31896687
2017 Coexpression of NUP98/TOP1 and TOP1/NUP98 in de novo Acute Myeloid Leukemia with t(11;20)(p15;q12) and t(2;5)(q33;q31). Cytogenetic and genome research 3 28249294
2014 Cloning of cDNAs for H1F0, TOP1, CLTA and CDK1 and the effects of cryopreservation on the expression of their mRNA transcripts in yak (Bos grunniens) oocytes. Cryobiology 3 24854867
2025 Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling. Nature communications 2 41145467
2023 Integrated multi-omics analyses reveal Jorunnamycin A as a novel suppressor for muscle-invasive bladder cancer by targeting FASN and TOP1. Journal of translational medicine 2 37587470
2010 Human TOP1 residues implicated in species specificity of HIV-1 infection are required for interaction with BTBD2, and RNAi of BTBD2 in old world monkey and human cells increases permissiveness to HIV-1 infection. Virology journal 2 21092135
2026 CRISPR/Cas9-mediated TOP1 knockout in chicken DF-1 cells reveals its critical role in apoptosis regulation and genomic stability. Journal of animal science 1 40971839
2025 Modulation of SUMO1-TOP1 DNA damage repair by TOPORS following ovalbumin-induced oxidative stress in macrophages. Toxicology letters 1 40532862
2023 Protective effects of hsa_circ_0072568 on interleukin‑1β‑stimulated human chondrocytes are mediated via the miR‑382‑5p/TOP1 axis. Experimental and therapeutic medicine 1 37456162
2022 Highly Purified Top1-Bound DNA Fragments. Methods in molecular biology (Clifton, N.J.) 1 35704193
2022 TOP1 inhibition induces bifurcated JNK/MYC signaling that dictates cancer cell sensitivity. International journal of biological sciences 1 35844787
2021 Critical roles of Rad54 in tolerance to apigenin-induced Top1-mediated DNA damage. Experimental and therapeutic medicine 1 33791014
1995 Assembly of nucleosomal DNA in a cell-free extract from wild-type and top1- strains of Ustilago maydis. Molecular & general genetics : MGG 1 7476870
1990 A three allele TaqI polymorphism at TOP1 gene. Nucleic acids research 1 1977141
2026 TOP1 and TOP2 complementarily maintain DNA replication fork progression in vertebrates. The Journal of biological chemistry 0 41791707
2026 Slx4 and Fun30/SMARCAD1 coordinate S-phase checkpoint regulation and replication fork protection in response to Top1-DNA crosslinks. Nucleic acids research 0 41978269
2026 Molecular Determinants of Response and Rational Drug Combinations for Antibody-Drug Conjugates (ADCs) with Topoisomerase I (TOP1) Inhibitor Payloads. Journal of molecular biology 0 42092629
2025 Compound Kushen Injection suppresses multiple myeloma progression via TOP1-targeted coordination of DNA damage and endoplasmic reticulum stress. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 40839989
2025 Discovery of Novel Drug-Conjugate Molecule ZM484 with Dual p53-MDM2 and TOP1 Inhibition for the Treatment of Colorectal Cancer. Journal of medicinal chemistry 0 40906370
2025 H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death. Cell death & disease 0 41315253

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